Human IBD probably results from a dysregulated mucosal immune response to normal intestinal bacteria. Substance P (SP) is a sensory neuropeptide produced and secreted by nerves and leukocytes in inflammatory bowel disease (IBD). We showed that SP is a Th1-type cytokine that functions through a T cell neurokinin 1 receptor (NK- 1R) to drive Th1 responses. T cell NK-1 R display appears up regulated in human IBD. In IL10-/- mice, piroxicam (a NSAID) induces chronic Th1 colitis and expression of NK-1 Ron gut T cells like seen in human IBD. Our data show that NK-1R inhibitors block ongoing inflammation in this animal model of colitis attesting to the importance of NK-1R in the inflammatory process. Moreover, several Th1-type cytokines (1L12, IL18, TNFalpha) induce T cell NK-1R expression, while others (IL10, TGFalpha) block its display suggesting that this receptor is subject to immune regulation. Thus, our overall hypothesis is that NK-1R, which is the major receptor for SP, is an inducible and highly regulated mucosal T cell receptor that helps drive the aberrant intestinal inflammation of IBD. Using piroxicam-induced IL10-/- colitis, which is an excellent IBD model, this proposal will further investigate these discoveries with three specific aims: Aim I derives from studies suggesting that SP acts directly on the T cell NK-1R to regulate Th1 responses. Therefore, using various transgenic mice developed in our laboratory, Aim I will explore the hypothesis that the NK-1R induced on T cells is critically important for regulating intestinal Th1 inflammation. Also, we showed that the T cell NK-1 R gene is subject to immune regulation. We postulate, based on preliminary data, that the various cytokines mentioned above primarily affect the NFkappaB pathway of cellular activation to govern T cell NK-1R gene transcription. Thus, using chemical inhibitors, transgenic mice and cells transfected with reporter gene and other vector constructs, Aim II will identify the intracellular signaling pathways that control NK-1R expression in T cells (mucosal, splenic and clones). We also postulate, as suggested by preliminary data, that NK-1R engagement results in receptor internalization and re-distribution, which is another important mechanism of NK-1R control in the mucosa and that cytokines regulate this process. Aim III will study how inflammatory mediators work to regulate T cell NK-1R cycling and function using T cell clones transfected with various probes and mucosal T cells. Strategies aimed at modulating NK-1 R function in the gut could prove therapeutically beneficial for IBD.